The androgen receptor (AR), a ligand-activated transcription factor and member of the nuclear receptor family, plays a key role in the development and progression of prostate cancer. While androgen deprivation therapy remains the cornerstone of clinical management for advanced and non-organ confined prostate cancer, the majority of patients undergoing this treatment eventually relapse. The recurrent disease is termed androgen independent or hormone refractory. Androgen independent tumors not only maintain transcriptionally active AR, they are dependent on AR for growth and survival even under androgen-depleted conditions. We and others have demonstrated that Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), is upregulated during in vitro and in vivo progression of prostate cancer to androgen-independence in several models as well as in men undergoing androgen deprivation therapy. Further, Vav3 protein is overexpressed in approximately one-third of human prostate cancer. We have demonstrated that Vav3, is a potent enhancer of AR transcriptional activity in prostate cancer cells in the presence or absence of androgen. Vav3 potentiation of AR transcriptional activity in the presence of androgen (coactivation) does not require Vav3 GEF activity. Further, our preliminary data show that Vav3 but not Vav3 W493L (a pleckstrin homology (PH) domain mutant) is recruited to an AR target gene androgen responsive region in chromatin. This recruitment occurs in an androgen-dependent manner and reveals a novel nuclear role for Vav3. In contrast, oncogenic (constitutively active) Vav3 (or Vav3 activated by growth factors) promotes ligand-independent AR activation via cross-talk that requires Vav3 GEF function and the Rho GTPase, Rac1. Thus, Vav3 is a versatile modulator of AR activity. Both the hormone-dependent and -independent activation of AR by Vav3 may contribute to prostate cancer progression and both pathways are exploitable therapeutically. The potential impact of this project is high due to the availability of drugs that inhibit Rac1. This study will investigate the mechanisms by which Vav3 enhances AR transcriptional activity and prostate cancer progression to androgen independence. We will determine whether Vav3/Rac1 signaling is necessary and sufficient to cause androgen independent tumor formation in tumor xenograft studies and in genetically engineered mouse models of prostate cancer. We will define the role of Vav3 enhancement of AR activity in this process. Identification of the molecular mechanisms of Vav3 potentiation of AR activity and examination of the contribution of Vav3 to prostate cancer progression in mouse models is essential for the development of Vav3 pathways as therapeutic targets. PUBLIC HEALTH RELEVANCE: RELEVANCE: Levels of the Vav3 protein rise in human prostate cancer. Vav3 enhances the activity of the androgen receptor, increases growth of prostate cancer cells and causes prostate cancer in mice. This study seeks to understand these oncogenic effects of Vav3 in order to exploit currently available drugs that target Vav3 pathways for prostate cancer therapy.